Summary/Abstract Aberration of vascular smooth muscle cell (SMC) phenotypes cause structural defects and impaired mechanical properties of artery wall, leading to artery stiffness, which correlates with high blood pressure and is an independent risk factor for the resistant hypertension. It is well-known that arterial wall stiffens with aging. In addition to hypertension, vascular aging is an independent risk factor for cardiovascular diseases including coronary artery disease, stroke and heart failure. However, the factors and mechanisms that control vascular aging, especially SMC aging and artery stiffness, remain largely unknown. Our exciting preliminary data demonstrate that Smad2 plays a critical role in maintaining SMC and vascular homeostasis and blood pressure. SMC-tissue specific deficiency of Smad2 (Smad2sm-/-) in mice causes alterations in elastin and collagen content and structure in the vessel wall, resulting in decreased artery distensibility, increased pulse pressure (indicator of artery stiffness), and increased mean artery pressure. The vascular wall remodeling/stiffness in Smad2 SMC- deficient mice appears to be caused by a premature SMC aging with an elevation in p53 level. In fact, the increase in p53 level along with the decrease in Smad2 expression in artery SMC correlates with the aging in mouse and human. Importantly, the correlation of decreased Smad2 with increased p53 is also closely associated with the onset of hypertension in human. These data strongly support a novel hypothesis that Smad2 maintains vascular homeostasis and blood pressure by inhibiting p53 expression and/or activity in SMC. Using primary culture of SMCs, in vivo Smad2 and p53 SMC-specific knockout mouse models combining with molecular, cellular, histological, and pharmacological approaches, we will 1) test if Smad2 is essential for maintaining the vascular wall elasticity and blood pressure homeostasis; 2) elucidate the mechanism by which Smad2 regulates SMC homeostasis through inhibiting p53 expression/activity; and 3) determine if blockade of p53 attenuates Smad2 deficiency-caused artery stiffness and hypertension. Successful completion of the proposed study will establish a novel mechanism regulating SMC aging and blood pressure homeostasis. It will also allow us to identify potential novel approaches that may be used to develop effective therapeutics for treating aging or artery stiffness-related hypertension.